Daniel Castellano Oncología Médica.Unidad de Tumores GenitoUrinarios
Guillermo Lerzo Especialista en Oncología INTRODUCCIÓN A LA INMUNOTERAPIA.
Transcript of Guillermo Lerzo Especialista en Oncología INTRODUCCIÓN A LA INMUNOTERAPIA.
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Guillermo LerzoEspecialista en Oncología
INTRODUCCIÓN A LA INMUNOTERAPIA
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Tumor Immunology: Overview
Dendritic cell
TUMOR
perforingranzyme cytokines
Activated T cell
T cell clonal expansion
Resting T cell
LYMPH NODE
TCR CD28
MHCB7
Tumor antigen
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Weiner LM. N Engl J Med. 2008;358:2664-2665.
Tumor-Derived Immune Suppression
• Tumors go to great lengths to evade the immune response.• Systematic studies have identified multiple mechanisms
cancers employ to defeat the immune response:– Immunosuppressive cytokines: TGF-β, IL-4, -6, -10.– Immunosuppressive immune cells: T-regs, macrophage.– Disruption of immune activation signaling: loss of MHC
receptor, IDO production.• Goal: therapy strategies that “liberate” underlying anticancer
immune responses.
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Immunotherapeutic approaches to breast cancer
Mary L. (Nora) DisisUniversity of WashingtonFred Hutchinson Cancer Research CenterSeattle, [email protected]
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Non-specificNo antigensNo memoryImmediateTransient
SpecificAntigensMemory
Slowly developingLifelong
Major categories of the immune system
drrajivdesaimd.com
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Clinically effective anti-tumor immunity
Fridman et al, Nat Rev Ca, 2012Bindea et al, Curr Opin Immunol, 2010
High magnitude Type ICD4 (Tbet+), CD8 (GZB+)
MemoryLow levels of regulatory cells
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Butt et al Oncogene, 2013
Increase effector T-cells Enhance existing immunity
TrastuzumabVaccines
Adoptive T-cell Therapy
Checkpoint inhibitorsCytokine Therapy (IL-15, IL-7)
Depletion Tregs, MDSCMoAB (X-IL-10, TGFb)
Modulate the tumor microenvironment
Approaches to optimizing a therapeutic immune response
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Topalian et al, JCO,
ActivateStimulatory signals
SuppressInhibitory signals
What is the optimal receptor-ligand interaction to target?
Use early in treatment course in a subset of breast cancer: mutation status, high levels of TIL?
****
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Butt et al Oncogene, 2013
Increase effector T-cells Enhance existing immunity
TrastuzumabVaccines
Adoptive T-cell Therapy
Checkpoint inhibitorsCytokine Therapy (IL-15, IL-7)
Depletion Tregs, MDSCMoAB (X-IL-10, TGFb)
Modulate the tumor microenvironment
Approaches to optimizing a therapeutic immune response
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Naive Prior/Concurrent
Ba
selin
e I
FN
R
esp
on
se(c
SP
W/1
06 P
BM
C)
ICD ECD ICD ECD0
500
1000
1500
20002000
5000
< 0.0001
< 0.0001
p
p
n=97, Stage III/IV HER2+ Stanton et al, 2014
Trastuzumab induced Type I immunity
Ferris et al, JCO, 2010
IFN-g secretion
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Disis et al, CCR Focus, 2013
Immunotherapeutic approaches to breast cancer
Tumor immune environment
•Level of TIL•Phenotype of TIL(Type I, II and regulatory)
Provide Type I immunityElicit Type I immunityRelease Type I immunity
Propagate immune response
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Associate Professor Sherene Loi, MD, PhDConsultant Medical OncologistHead, Translational Breast Cancer Genomics and Therapeutics labPeter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Tumor Infiltrating Lymphocytes (TILs) in Breast Cancer
San Antonio Breast Cancer Symposium, December 9-13, 2014
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
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What is the evidence that immunity is important in breast cancer?
• Breast cancer incidence increases in age
• Breast cancer in young women is more aggressive
• Immunosuppressed patients have worse outcomes from breast cancer
• TILs and immune-related gene signatures have been shown to have associations with prognosis in some breast cancer subtypes
• Objective responses to T cell checkpoint inhibitors have observed in breast cancer (data this meeting)
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
San Antonio Breast Cancer Symposium, December 9-13, 2014
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Tumor infiltrating lymphocytes (TILs)- why evaluate TILs?
• First publication in EJC in 1992 Aaltomaa et al 1992
• Immune gene signatures are associated with prognosis in ER-negative breast cancer Desmedt et al, 2008; Teschendorff et al 2007; Alexe et al,2007; Rody et al 2009
• TILs represented a feasible way of evaluating the prognostic and predictive role of immunity in large cohorts of well annotated breast cancer samples (ultimate marker will depend on clinical utility)
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
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Predefined parameters for TILs evaluation
intratumoral TILs =direct contact to tumor cells
stromal TILs = between the tumor cells
LPBC = Lymphocyte-predominant breast cancer„more lymphocytes than tumor cells“ (≥60% TILs /≥50% TILs )
TLS (tertiary lymphoid structures)= follicular aggregates outside of the tumor
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
Courtesy C Denkert
Salgado, Denkert et al, Guidelines for TILs Evaluation in Breast Cancer- Annals of Oncology 2014
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intratumoral TILs =direct contact to tumor cells
stromal TILs = between the tumor cells
LPBC = Lymphocyte-predominant breast cancer„more lymphocytes than tumor cells“
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
Courtesy C Denkert
Salgado, Denkert et al, Guidelines for TILs Evaluation in Breast Cancer- Annals of Oncology 2014
Predefined parameters for TILs evaluation
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Higher levels in HER2+ and TNBC
Loi et al, JCO 2013; Ann Oncol 2014This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
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Higher TILs=better survival in primary TNBC
P=0.01
MFS OS
Post-neoadjuvant setting in TNBC
Dieci et al, AoO 2014; Loi et al, JCO 2013; AoO 2014
Primary TNBC, prior to Chemo
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TILs prognostic in HER2+ treated with anti-HER2 agents and CT
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
Unpublished data- NeoALTTO study
For every 1% increase in TILs, 3% decrease in risk of an event, independent of treatment arm (trastuzmab, lapatinib and combination).
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Clinical implication of TILs
• Pre-existing host anti-tumor immune responses
• The more you have, the better outcome from 1. Primary HER2+ breast cancer treated with anti-HER2 agents and chemo2. Primary TNBC treated with adjuvant anthracycline-based chemo3. Probably also in metastatic disease
• Role in clinical decision making?• Role in predicting response to T cell checkpoint inhibitors and other
immunotherapies
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
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Converting tumors from low TILs into high TILs
• Immunogenic chemotherapy- anthracyclines, metronomic chemo, gemcitabine
• Radiotherapy can drive a T cell response.– Dose and schedule
could be critical– Combinations with
immunotherapies could be beneficial
Verbrugge et al 2012; Dewan et al, 2009; Klug et al, 2013BOSTON-II study- NCT02303366
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Conclusions
• TILs represent functional pre-existing Th1 immunity
• Why some breast cancers do and do not have varying levels of TILs remains to be elucidated
• Role of TILs in clinical decision making– Analytical validity of TILs biomarker ongoing– Clinical utility of TILs remains to be determined
• However prognostic associations of TILs supports the concept that immune approaches may improve outcome in HER2+ BC and TNBC– TNBC- combination therapy
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
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Abstract S1-06: Edith A. Perez et al.
• Stromal tumor-infiltrating lymphocytes (Str-TILs): In the Alliance N9831 trial Str-TILs are associated with chemothetapy benefit but not associated with trastuzumab benefit.
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N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy.
• 945 patients with HER2 positive breast cancer.• 3 Arms: A. AC – T B. AC – T – H C. AC – T + H- Str-TILs defined as % tumor stromal that
contains lymphocytic infiltrate (LI).- Str-TILs measurements: > 60% classified as
“lymphocyte predominant breast cancer (LPBC).
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Univariable Str-TILs Results (1)• Tumors with high Str-TILs were more likely to be hormone
receptro negative (p< 0.0001)• In Arm A (chemotherapy): - LPBC patients: 10ys RFS = 90.9%. - non-LPBC patients: 10ys RFS = 64.3%. - HR = 0.22; 95% CI 0.07 to 0.68, p=0.009. In Arm C (chemptherapy + trastuzumab): - LPBC patients: 10ys RFS = 80.0% - non-LPBC patients: 10ys RFS = 79.6%. - HR = 1.13;95% CI 0.45 to 2.84, p=0.79.
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Univariable Str-TILs Results (2)
• In LPBC patients group (Str-TILs > 60%): - Arm A: 10ys RFS = 90.9%. - Arm C: 10ys FRS = 80.0%. - HR = 2.43%; 95% CI 0.58 to 10.22, p = 0.22.. In non-LPBC patients group (Str-TILs < 60%): - Arm A: 10ys RFS = 64.3%. - Arm C: 10ys RFS = 79.6%. - HR = 0.49; 95% CI 0.35 to 0.60, p<0.0001.
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Str-TILs: Multivariable Results.• Variables: nodal status, HR status, tumor size, tumor grade, age.. Dichotomous cutoff of Str-TILs: LPBC status - associated with RFS in Arm A HR= 0.19;95% CI 0.66 to 0.61, p=0.005 - not associated with RFS in Arm C HR= 1.01; 0.95% CI 0.39 to 2.6, p=0.98. Increasing Str-TILs deciles - associated with RFS in Arm A (p<0.0001) - not associated with RFS in Arm C (p=0.13)
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CONCLUSIONS• Provocative results: - increasing % Str-TILs correlates with benefit of chemotherapy in early stage HER2+ BC. - impact of adding adjuvant trastuzumab not as clear in patients with LPBC.. Plans: corroborate in a separate cohort. . Identify subtypes of Str-TILs. . Correlate Str-TILs with inmune gene profiles. . Determine whether changing the amount and type
of Str-TILs will improve patients outcome.
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Str-TILs in Early Stage HER2+ BC:Conclusions.
• Increasing Str-TILs associated with increased RFS in pts treated with chemotherapy.
- not foun to be associated with increased RFS in pts treated with chemotherapy plus trastuzumab.
. Patients with non-LPBC had better RFS when treated with chemotherapy + trastuzumab compared to chemotherapy alone.
- but pts with LPBC did not have better RFS when treated with chemotherapy + trastuzumab than chemotherapy alone.
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Checkpoint Protein Inhibition
2014 San Antonio Breast Cancer Symposium
San Antonio, TX December 9th, 2014
Jeffrey Weber M.D. Ph.D.Moffitt Cancer Center
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Immune Checkpoint Pathways
CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4 ; MHC = major histocompatibility complex; PD-1 = programmed death-1;PD-L1 = programmed death ligand 1; TCR = T-cell receptor.
31
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Immunotherapy for breast cancer: Myth or Fact?
• Tumor infiltrating lymphocytes (TIL) in primary triple negative breast cancer after neo-adjuvant chemotherapy are associated with better RFS, DMFS, OS1
• TIL in stroma and tumor tissue are associated with RFS and OS after adjuvant chemotherapy2
• PD-L1 expression and TIL in primary breast cancer are associated with a better outcome3
• Myeloid derived suppressor cells are associated with high likelihood of nodal metastases in breast cancer4
1: Adams, S et al JCO 2014 2: Loi, Y et al JCO 2013 3: Schalper, K et al CCR 2014 4: Yu, J et al J Immunol 20132
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PD-1/PD-L1 blocking agents in development
• Pembrolizumab - humanized IgG4 anti PD-1 antibody, approved for second line therapy of melanoma
• Nivolumab, human IgG4 anti PD-1 antibody, approval for melanoma pending
• MPDL-3280A, humanized PD-L1 antibody
• MEDI 4736, human IgG1 PD-L1 antibody
• AMP 224, fusion of Fc and anti-PD-L1
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Immunotherapy for breast cancer: Myth or Fact?
• Tumor infiltrating lymphocytes (TIL) in primary triple negative breast cancer after neo-adjuvant chemotherapy are associated with better RFS, DMFS, OS1
• TIL in stroma and tumor tissue are associated with RFS and OS after adjuvant chemotherapy2
• PD-L1 expression and TIL in primary breast cancer are associated with a better outcome3
• Myeloid derived suppressor cells are associated with high likelihood of nodal metastases in breast cancer4
1: Adams, S et al JCO 2014 2: Loi, Y et al JCO 2013 3: Schalper, K et al CCR 2014 4: Yu, J et al J Immunol 20132
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PD-1 blockade: Myth or Fact?• PD-L1 staining is a predictive marker useful
for choosing melanoma patients for PD-1/PD-L1 blockade• There appears to be an association between ORR
and tumor PD-L1 positivity by IHC in most trials• Patients may still respond even if tumor PD-L1
staining is negative• Equivocal data on association of PD-L1 staining
with overall survival.
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PD-L1 expression and response rate
N PDL1 + Positive
PDL1 - Negative
Nivolumab (Topalian, NEJM, 2012)
42 9/25 (36%) 0/17 (0%)
Nivolumab (Weber #9011)
44 8/12 (67%) 6/32 (19%)
MPDL3280A (Hamid #9010)
30 4/15 (27%) 3/15 (20%)
Nivolumab/ Ipilimumab (Callahan #3003)
27 4/10 (40%) 8/17 (47%)
Nivolumab (Grosso #3016)
34 7/16 (44%) 3/18 (17%)
Urba, W ASCO 2014
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Efficacy Based on Tumor PD-L1 Expression (Central Review, RECIST v1.1)
Presented by: Richard Kefford, ASCO 2014
a1-sided P values calculated by logistic regression, adjusting for dose/schedule.PD-L1 positivity defined as staining in ≥1% of tumor cells.Analysis cut-off date: 18 October 2013.Daud A et al. Presented at: 2014 Annual AACR Meeting; April 5-9, 2014; San Diego, CA.
P = 0.0007a
8060402000
20
40
60
80
100
PFS,
%
Time, weeks
PD-L1+
PD-L1–P = 0.0051
8060402000
20
40
60
80
100
Time, weeks
OS,
%
PD-L1+
PD-L1–
P = 0.3165
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Overall survival based on tumor PD-L1 expression by IHC does appear to favor PD-L1+ tumors
Ribas, A et al SMR 2014
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Conclusions: Checkpoint protein inhibition for breast cancer
• Many different histologies now respond to checkpoint protein inhibitory drugs, including breast cancer!
• Slow regression, progression prior to regression are common in immuno-oncology and require new response criteria to accommodate irRC responses.
• Immune related adverse events are a new field for toxicity management and require a learning curve.
• Prolonged duration of response and plateauing of survival curves suggest that cures are possible.
• The Law of Unintended Consequences suggests that new and unexpected toxicities will occur.
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Clinical Development of Inhibitors of PD-1 Immune Checkpoint
Target Antibody Molecule Development stage
PD-1
Nivolumab(BMS-936558) Fully human IgG4
Phase III multiple tumors (melanoma, RCC, NSCLCa,
HNSCC)
Pembrolizumab(MK-3475) Humanized IgG4 Phase I-II multiple tumors
Phase III NSCLC/melanoma
Pidilizumab(CT-011) Humanized IgG1 Phase II multiple tumors
PD-L1
MEDI-4736 Engineered human IgG1 Phase I-II multiple tumors
MPDL-3280A Engineered human IgG1 Phase I-II multiple tumorsPhase III NSCLC
MSB0010718C Fully human IgG1 Phase I solid tumors
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Abastract S1-09: Rita Nanda et al.• A phase IB study of pembrolizumab (MK-3475) in
patients with advanced triple-negative breast cancer. University of Chicago, IL.
• Pembrolizumab (MK-3475) is a humanized IgG4, High-Affinity, Anti-PD-1 Antibody:
- High affinity for the PD-1 receptor. - Dual ligand blockade of PD-L1 and PD-L2. - No cytotoxic activity. - PK supports dosingevery 2 weeks or every 3 weeks. - Demostrated clinical activity in multiple tumor types.
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KEYNOTE-012: triple-negative breast cancer cohort.
• Recurrent or metastatic triple-negative BC.• ECOG PS 0 – 1.• PD-L1 tumor expression was assesed: 58% of all pts.• No systemic steroid therapy.• No autoimmune disease.• No active brain metastasis.• Response assesment every 8 weeks.• Treatment: Pembrolizumab 10 mg/kg iv Q2W.
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Treatment-Related Adverse Events with Incidence >5%.
• Any grade: arthralgia 18.8% fatigue 18.8% myalgia 15.6% nausea 15.6% ALT/AST increased 6.3% diarrhea 6.3% erythema 6.3% headhache 6.3%
. Grade 3-4: headhache 3.1%
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Best Overall Response (RECIST 1.1)• Overall response rate: 5 (18.5%)• Best overall response: - complete response 1 (3.7%) - partial response 4 (14.8%) - stable disease 7 (25.9%) - progressive disease 12 (44.4%) - no assesment 3 (11.1%)* 66% pts > 4 lines for metastatic disease.
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Pembrolizumab: summary.• Pembrolizumab showed an acceptable safety and
tolerability profile in pts with heavily pretreated, PD-L1-positive. Advanced triple-negative breast cancer.
• Pembrolizumab was associated with an OOR of 18.5%.• Response was durable, with the median response
duration not reached (range, 15 to 40+ weeks) and 3 of 5 responders on treatment for >11 months.
• The acceptable safety and tolerability profile and promising antitumor activity support the further development of pembrolizumab in patients with advanced triple-negative breast cancer.
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